In certain instances numerous pharmacogenetic disorders in man cause individuals to react very differently to the same dose of the same drug. The teratogenic, carcinogenic, or toxic effects of certain drugs and other foreign compounds (xenobiotics) may also reflect important genetically mediated differences between individuals. Accordingly, our laboratory has developed experimental model systems for studying drug metabolism in cell culture and in a colony of inbred strains of mice. We have determined that the induction of at least 14 drug-metabolizing enzyme activities is regulated at one or two genetic loci, called the Ah locus for aromatic hydrocarbon responsiveness. The relative presence of "aromatic hydrocarbon responsiveness" in certain mice results in more polycyclic hydrocarbon-initiated tumors, in a shortened paralysis time when given a certain muscle relaxant, in a shortened survival time when dosed with large amounts of polycyclic hydrocarbons, in hepatic necrosis and cataract formation when given acetaminophen, and in an increased number of fetal resorptions, stillbirths, and malformations when the pregnant mother is given certain chemicals. These genetically mediated dissimilarities in xenobiotic metabolism may be a useful probe in demonstrating differences in the rates of certain drug-induced birth defects. BIBLIOGRAPHIC REFERENCES: Felton, J.S., Nebert, D.W., and Thorgeirsson, S.S.: Genetic differences in 2-acetylaminofluorene mutagenicity in vitro associated with mouse hepatic aryl hydrocarbon hydroxylase activity induced by polycyclic aromatic compounds. Mol. Pharmacol. 12: 225-233, 1976. Nebert, D.W., and Felton, J.S.: Importance of genetic factors influencing the metabolism of foreign compounds. Fed. Proc. 35: 1133-1141, 1976.